Background: PIWI-interacting RNAs (piRNAs) have emerged as regulators of tumor biology, but their roles in pancreatic ductal adenocarcinoma (PDAC) remain unclear. We investigated the function and downstream molecular context of piR-016176 in PDAC. Methods: piRNA profiling was performed in 10 paired PDAC and adjacent tissues, followed by validation in an independent cohort of 50 paired specimens and PDAC cell lines. Gain- and loss-of-function assays assessed cell viability, migration, invasion, and apoptosis. Data-independent acquisition proteomics, bidirectional rescue experiments, computational analyses, and PIWIL1 RNA immunoprecipitation (RIP)-qPCR were used to identify and evaluate downstream effectors. Acetylome profiling after SAP18 depletion and integrated RNA-seq/proteomic analysis after piR-016176 overexpression were performed to characterize associated molecular programs. Results: piR-016176 was significantly downregulated in PDAC tissues and cell lines. Its overexpression reduced cell viability, migration, and invasion and promoted apoptosis, whereas inhibition produced opposite effects. SAP18 was reciprocally regulated by piR-016176, and bidirectional rescue experiments supported SAP18 as a functional mediator. RIP-qPCR showed enrichment of both piR-016176 and SAP18 mRNA in PIWIL1-associated ribonucleoprotein complexes. SAP18 depletion altered 185 acetylation sites, including 181 increased and four decreased sites, in proteins enriched for RNA regulatory and mitochondrial metabolic functions. Integrated transcriptomic and proteomic analyses identified 112 concordantly upregulated targets after piR-016176 overexpression, with enrichment in interferon- and immune-related programs. Conclusions: piR-016176 acts as a tumor-suppressive piRNA in PDAC, with SAP18 functioning as a downstream mediator. These findings implicate PIWIL1-associated regulation, acetylation remodeling, and interferon-related programs in this regulatory framework and warrant further mechanistic validation.